Pediatric massage therapy for treatment of tic disorders in children: A systematic review and meta-analysis of randomized controlled trials

Background: Tic disorder is a common neurodevelopmental disorder in childhood, characterized primarily by motor or vocal tics. However, there is no systematic evaluation of pediatric massage therapy for children with Tic disorder. This study aims to evaluate the effectiveness and safety of massage therapy for children with tic disorder through a comprehensive meta-analysis and systematic review. Methods: We systematically searched relevant randomized controlled trials from various databases such as CBM, CNKI, VIP, Wanfang database, PubMed, Embase, Web of Science, Cochrane Library, and SINOMED, published up to October 2023. To collect randomized controlled trials on pediatric massage therapy or in combination with other therapies for the treatment of tic disorders in children. The risk of bias in the included articles was assessed using the Cochrane guideline. Meta-analyses were performed using Review Manager 5.4, and publication bias was evaluated by using Begg test and Egger test in Stata SE software. Results: This meta-analysis included 19 randomized controlled trials with 1423 patients. Pediatric massage therapy alone or in combination with conventional medication demonstrated a significant increase in clinical effectiveness rates [risk ratios = 1.15, 95% confidence interval [CI] (1.10, 1.20), Z = 6.54, P < .001], and reduced Yale Global Tie Severity Scale scores [standardized mean difference = −0.85, 95% CI (−1.50, −0.19), Z = 2.54, P = .01] and traditional Chinese medicine syndrome scores [standardized mean difference = −1.35, 95%CI (−2.08, −0.63), Z = 3.66, P = .0002]. In terms of adverse reactions, there was no statistical difference between the experimental and control groups [risk ratios = 0.26, 95% CI (0.14, 0.49), Z = 4.25, P < .001]. The Begg test and Egger test results indicated no publication bias. Conclusion: Evidence suggests that pediatric massage therapy is effective in improving tic disorders in children.


Introduction
Tic disorder (TD) is a common neurodevelopmental disorder in childhood, characterized primarily by motor or vocal tics. [1]According to DSM-5, [2] TD can be classified into provisional tic disorder, chronic motor or vocal tic disorder, and Tourette syndrome.According to a study by the Centers for Disease Control and Prevention, based on data from the 2007 National Survey of Children's Health, the estimated prevalence of a lifetime diagnosis of Tourette syndrome by parent report was 3.0 per 1000. [3]In China, the prevalence of TD is estimated at approximately 6.1%, with higher rates among boys than girls. [4]TD typically manifests in childhood with varying severity over time, and most children experience improvements in symptoms in late adolescence or early adulthood. [5]In children, tics can significantly impact school life and have lasting effects on emotional, social, and physical well-being until adulthood. [6]n Western medicine, colistin and guanfacine are used to treat TD, but these drugs often come with side effects such as drowsiness, lightheadedness, tiredness, irritability, and hypotension. [7]Cognitive-behavioral intervention for tics is effective in reducing tic severity and improving the quality of life in Chinese children and adolescents with TD, though finding a trained doctor can be challenging. [8]Additionally, parents of children with special medical needs use a complementary or alternative method for treatment. [9]Therefore, it is essential to identify an effective complementary or alternative approach to address TD.
Massage therapy is one of the widely used alternative therapies.Pediatric massage therapy, rooted in Chinese medicine with modern scientific principles, employs specific techniques to stimulate body acupuncture points and meridians to achieve therapeutic purposes.[12][13][14][15] From the perspective of traditional Chinese medicine (TCM), the pathogenesis of TD in children is hyperactivity of Yang and disharmony of Yin and Yang.Massage aims to restore yin and yang balance.It may be achieved through the stimulation of pressure receptors, resulting in increased vagal activity and reduced cortisol levels. [16]However, there are some limitations, as results vary from doctor to doctor due to different practices.Previous studies seem to indicate that massage therapy, in combination with medication or alone, is effective in improving neurobehavioral disorders in children and has fewer side effects compared to medication. [17]In recent years, a growing number of researchers have explored pediatric massage to treat children with TD, but there is no systematic evaluation of pediatric massage therapy for children with TD.Therefore, we conducted a comprehensive systematic review and meta-analysis based on existing evidence to summarize the evidence of the efficacy and safety of massage therapy for TD in children.This meta-analysis will provide an evidence-based medical basis for pediatric massage therapy in the treatment of childhood tic disorders, bring guidance for clinicians, inspire ideas for researchers, and benefit more patients.

Materials and methods
This study was performed following the PRISMA 2020 (The Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020) guideline [18] and registered on PROSPERO (Registration ID: CRD42023396999).This study was based on a statistical analysis of the published literature, it was not necessary to review it by an ethics committee or an institutional board.

Retrieval method
A comprehensive search of scientific databases was conducted to identify relevant articles, with no language restrictions.The search period is from the inception of the databases to October, 2023.Both subject words (MeSH) and free words were used for the search.The subject terms included "Tic Disorders" [Mesh] and "Massage" [Mesh]; the keywords were: "Tic Disorder" OR "Chronic Motor or Vocal Tic Disorder" OR "Tic Disorder, Chronic Motor or Vocal" OR "Motor or Vocal Tic Disorder, Chronic" OR "Transient Tic Disorder" OR "Transient Tic Disorders" OR "Childhood Tic Disorders" OR "Childhood Tic Disorder" OR "Tic Disorder, Childhood" OR "Tic Disorders, Childhood" OR "Motor Tic Disorders" OR "Motor Tic Disorder" OR "Tic Disorder, Motor" OR "Tic Disorders, Motor" in combination with "Massage" OR "Zone Therapy" OR "Therapies, Zone" OR "Zone Therapies" OR "Therapy, Zone" OR "Massage Therapy" OR "Massage Therapies" OR "Therapies, Massage" OR "Therapy, Massage."The search strategy is shown in Annex S1, Supplemental Digital Content, http://links.lww.com/MD/L946.

Literature screening and data extraction.
Two investigators (JQ Wu and FS Yang) independently screened the literature.The retrieved studies were imported into EndNote X9 to remove duplicate records.Then, the titles and abstracts were checked to filter out irrelevant literature.The full texts of the remaining studies were downloaded and comprehensively read to select eligible studies.In case of any disagreements, a third reviewer (LP Sun) was consulted to discuss and resolve the discrepancies.Relevant data such as first author, country, study design, year of publication, sample size, age of subjects, gender, duration of disease, duration of treatment, method of intervention, duration of follow-up, and outcome indicators were extracted from the included studies.

Risk of bias assessment
Two independent reviewers (JQ Wu and FS Yang) assessed the methodological quality and risk of bias in the included randomized controlled trials (RCTs) using the Cochrane risk of bias tool.The quality assessment involves the following domains: random sequence generation, allocation concealment, blinding methods, incomplete outcome data, selective outcome reporting, and other bias sources.The risk of bias was classified as "low," "high," or "unclear." [19]The kappa value of the reviewers who extracted the data was analyzed using spss 27.0 and the kappa value was 0.869, suggesting good consistency.

Statistical analysis
This meta-analysis was performed using the RM 5.4 software.Dichotomous variables were expressed as the odds ratio or risk ratio (RR) with 95% confidence interval (CI), whereas continuous variables were displayed as the mean difference or standardized mean difference (SMD) with 95% CI.Statistically significant differences were considered when the P-value was <.05.The heterogeneity of the study results was determined based on the Chi² test, and the values of I² > 25%, 50%, and 75%, indicated low, moderate, and high heterogeneity, respectively.If I² is <50%, the heterogeneity can be ignored.In cases where studies exhibited statistical homogeneity (I 2 < 50%, P > .1),meta-analysis was performed using a fixed effects model.If there was significant heterogeneity (I 2 ≥ 50%, P < .1),meta-analysis was performed using the random effects model, and the source of heterogeneity was further examined by sensitivity analysis, subgroup analysis, or similar techniques.www.md-journal.com

Publication bias
When the number of included RCTs for an outcome measure was ≥10, Begg test, Egger test and funnel plots were employed to assess the potential publication bias of RCTs. [20,21] Results

Basic characteristics and quality evaluation of the included RCTs.
A total of 19 RCTs [22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40] published in Chinese were included in the analysis.There were 1423 participants, with 711 individuals  Regarding the potential for selection bias, 7 studies [22,25,27,29,30,32,37] employed the random number table method and were rated as having a low risk of bias.One study [39] assigned participants randomly based on the order of visit and was rated as having a high risk of selection bias.The remaining studies did not report the method to generate random sequences, thus categorized as an unclear risk.For allocation concealment bias, 2 studies [27,37] used the sealed envelope bag and were rated as having a low risk.The remaining studies did not report allocation concealment, resulting in an unclear risk.All studies did not report performance bias and detection bias, leading to an unclear risk.For attrition bias, all studies reported prespecified endpoints and were rated as having a low risk.For reporting bias, all studies reported prespecified endpoints and were rated as having a low risk.As for other potential biases, all studies did not provide relevant information, resulting in an unclear risk.The plot for risk of bias is shown in Figure 2.

Meta-analysis results
The meta-analysis results are shown in Table 2.

3.3.1.
Clinical effective rates.Among the selected literature, 18 articles [22][23][24][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40] reported clinical effectiveness rates with a total of 1333 cases, including 666 cases in the experimental group and 667 cases in the control group. No sigificant heterogeneity was detected (P = .48,I 2 = 0%), and thus a fixed effect model was chosen to combine the effect sizes [RR = 1.15, 95% CI (1.10, 1.20), Z = 6.54,P < .001].According to the forest plot, the diamond weights did not intersect with the null line and were located at the right of the null line, indicating that the clinical effectiveness rate of the experimental group was significantly higher than that of the control group.The results of the metaanalysis of clinical effective rates are shown in Figure 3.
Given the high level of heterogeneity, a sensitivity analysis was performed to investigate potential sources of heterogeneity.These studies were excluded one by one and the results are summarized in Table 3.
Further exclusion of 3 articles by Zhang L.L, Zhang X.J, Song HL, caused even lower heterogeneity (I 2 = 50%), and the random effect model was used for meta-analysis [SMD = −0.40,95% CI (−0.64, −0.17), Z = 3.39, P = .0007].The results of meta-analysis are shown in Figure 6.As shown in the forest plot, the weighted rhombus did not intersect with the null line and was located to the left of the null line, suggesting that the overall efficacy rate of pediatric massage alone or in combination with conventional drug medication was higher than that of conventional drug medication alone in treating children with TD.

TCM syndrome scores.
Eight studies [22,24,25,30,[37][38][39][40] reported TCM evidence points, with 282 cases in the experimental group and 284 cases in the control group.The analysis demonstrated high heterogeneity (I² = 93%), and thus the random effect model was chosen to combine the effect sizes [SMD = −1.35,95% CI (−2.08, −0.63), Z = 3.66, P = .0002].Moreover, the TCM syndrome score in the experimental group were significantly lower than that in the control group.The forest plot for TCM syndrome score is shown in Figure 7.
Furthermore, given the high heterogeneity in this outcome indicator, a sensitivity analysis was conducted to explore potential sources of heterogeneity.The included studies were excluded one by one, and the results are shown in Table 4.
When the study of Tian X was excluded, the heterogeneity of the remaining studies was significantly reduced (I 2 = 87%).The forest plot analysis using a random-effects model and combined sizes demonstrated [SMD = −0.90,95% CI (−1.41, −0.39), Z = 3.45, P = .0006](Fig. 8).Moreover, excluding 3 studies by Yang L, Tian X, and Yang XY, resulted in even lower heterogeneity (I 2 = 54%), and the random effect model was chosen to combine the effect sizes [SMD = −0.88,95%CI (−1.21, −0.54),Z = 5.12, P < .001].The results are shown in Figure 9.As shown in the forest plot, the weighted rhombus did not intersect with the null line and was located to the left of the null line, suggesting that pediatric massage alone or in combination with conventional drug medication was superior The summary of the current meta-analysis results.to medication alone in improving the TCM syndrome scores of children with TD.

Publication bias
Publication bias analysis was performed for the primary outcome indicator of clinical efficacy.As indicated in Figure 11, the funnel plot was symmetrical.Begg test (P = .12)and Egger test (P = .855)were performed and showed no evidence of bias detected, as shown in Figures 12 and 13, respectively.

Sensitivity analysis
In our meta-analysis, the included RCTs were generally homogeneous.The primary outcome indicator was clinical efficacy, while YGTSS scores, TCM syndrome scores and adverse effects were classified as secondary outcome indicators.According to the meta-analysis data, the heterogeneity for YGTSS scores and TCM syndrome scores was high, prompting to carry out sensitivity analysis to investigate the source of heterogeneity.Furthermore, after excluding 3 articles by Zhang L.L, Zhang X.J, and Song HL, the remaining studies exhibited significantly reduced heterogeneity (I 2 = 50%).In terms of TCM syndrome   scores, when the 3 articles by Yang L, Tian X, and Yang XY were excluded, the heterogeneity of the remaining studies decreased (I 2 = 54%).

Discussion
Pediatric massage is a widely physical therapy for treating TD in children.However, its effectiveness and safety have not been systematically evaluated.To the best of our knowledge, this is the first study to summarize the current evidence on the use of massage for the treatment of TD.This meta-analysis of 19 RCTs    It is worth noting that there have been relatively fewer studies on massage therapy for TD.Chen SC et al [15] conducted a meta-analysis of 4 studies, which indicated that massage therapy was beneficial in treating attention deficit hyperactivity disorder in children and adolescents.Both TD and attention deficit hyperactivity disorder are childhood neurodevelopmental disorders, [41] which implies that our findings are similar to the previous study.
Pediatric massage is performed based on the meridian theory, in which the manipulation, strength, and direction of specific acupuncture points can produce diverse therapeutic effects for various diseases.According to traditional Chinese medicine theory, children have predominantly Yang-based constitutions, characterized by excess yang energy and a relative deficiency of essence, blood, and fluid.This imbalance is thought to contribute to the onset of TD.Pediatric massage can strengthen the spleen, soften the liver, and nourish the yin to calm the wind.Regarding the biological mechanism of massage, some studies have found that the application of massage techniques leads to cyclic dynamic changes in tissue pressure.This, in turn, induces changes in osmolality, osmotic factor, and the apparent viscosity of blood in capillaries, promoting better blood circulation and substance exchange.
This meta-analysis exhibits several limitations.First, the relatively small sample size could potentially impact the accuracy of the study results.Since all the included studies were conducted in China, the results might not be applied to different populations.Second, a majority of the included studies did not provide explicit details about their randomization, hidden allocation, or blinding method, which may undermine the reliability of the evidence to a certain extent.Third, there are multiple diagnostic criteria for TD, and the 19 papers included in this study have employed various textbooks, guidelines, and other diagnostic criteria.The lack of standardization in diagnostic criteria introduces heterogeneity in the systematic research, potentially affecting the results.
Large-scale, multicenter studies are desired to validate the results of this meta-analysis.Furthermore, extending the follow-up period to explore the long-term effects of pediatric massage therapy and its potential mechanism of action could offer a more comprehensive understanding of its feasibility as a physical therapy for tic disorders.

Conclusion
In conclusion, this meta-analysis highlights the potential efficacy and safety of pediatric massage therapy for Tic disorders in children.However, it is important to note that that the included studies exhibited overall low methodological quality and had limitations in the control design.Hence, further research with improved methodological designs is crucial to corroborate the efficacy and safety of massage as a treatment for tic disorders in children.

Figure 2 .
Figure 2. The plot for risk of bias.

Figure 3 .
Figure 3. Forest plot for clinical effective rates.

Figure 7 .
Figure 7. Forest plot for TCM syndrome score.TCM = traditional Chinese medicine.

Table 1
Basic information of the included literature.④adversereaction.www.md-journal.com in the experimental group and 712 individuals in the control group.All the studies were conducted in China.The control group received conventional drug therapy, and the experimental group was given massage therapy alone or combined with conventional drug therapy.The duration of treatment ranged from 4 to 12 weeks.The detailed features of the included studies are shown in Table1.

Table 3
Results of the study after one-by-one exclusion.

Table 4
Results of TCM syndrome scores after one-by-one exclusion.